Alzheimer's Disease (AD) is a progressive neuro-degenerative disease that affects over 5.5 million aged Americans and their 13 million caregivers. While the exact cause of AD in sporadic patients is unknown, enzymes and proteins that increase in the AD state are logical targets for drug development. Ornithine Decarboxylase (ODC) is the rate- limiting enzyme for the synthesis of polyamines. In addition to ODC itself, levels of polyamines are also significantly increased in AD brains compared to age-matched controls. Polyamines have been associated with increased NMDA-mediated excitotoxicity, decreased inward rectifier activity, and increased aggregation of the amyloid beta peptide (A). All of these activities can contribute to neuronal loss in the AD brain. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ODC that is off-patent and has been shown to reduce brain levels of polyamines. However, gastrointestinal toxicities preclude dosing DFMO at high levels, which is why DFMO is typically intravenously infused in patients with sleeping sickness. We propose synthesizing novel prodrugs based upon the DFMO-parent molecule that will be absorbed in the gut, but do not cause gastrointestinal toxicities. Once these prodrugs are in the blood stream, esterases in the blood will cleave off the extra chemical groups to allow the DFMO inhibitor of ODC to circulate. From our own experiments and those of others, DFMO crosses the blood brain barrier to enter the brain and inhibit brain ODC. In preliminary data, we showed that administration of DFMO to the CVN mouse model of Alzheimer's disease significantly improves their learning and memory behavior while reducing amyloid plaque-like and neurofibrillary tangle-like structures. In addition, another group recent reported similar therapeutic effects of DFMO administration in another mouse model of AD. The extensive use of DFMO in humans with other diseases plus these new data support that prodrugs based on DFMO may be effective anti-Alzheimer's agents. The prodrugs that we are proposing to synthesize are novel, and pending successful testing for activity as detailed in this proposal, wil be useful, which are the two main criteria for patenting theses new compositions of matter and their field of use.
Orally-Available Prodrugs for Alzheimer's Disease (AD) AD is a progressive neuro-degenerative disease that affects over 5.5 million aged Americans and their 13 million caregivers. One enzyme that significantly increases in AD patients is ornithine decarboxylase or ODC. ODC is the rate-limiting enzyme in the production of polyamines, which are also significantly increase in AD brains. Polyamines enhance neuronal death in the brain where they contribute to neuronal death in AD. We propose to create and test novel prodrugs that can be orally delivered to AD patients without gastrointestinal toxicities, will reduce ODC activity, will reduce polyamine levels and will reduce neuronal death in AD, which should lead to improved learning and memory in AD patients.
|Mukherjee, Shubhabrata; Walter, Stefan; Kauwe, John S K et al. (2015) Genetically predicted body mass index and Alzheimer's disease-related phenotypes in three large samples: Mendelian randomization analyses. Alzheimers Dement 11:1439-1451|